Breast cancer (BrCa) is the most common malignancy in women; one-in-eight women will develop breast cancer during their lifetime. Mortality from breast cancer in the U.S. has been on the decline that is mostly attributed to effective systemic adjuvant therapies. However, there are still numerous deaths from breast cancer each year. Therefore, there is a significant unmet need to improve systemic therapies. Rac, a member of the Rho family GTPases, is commonly overexpressed in cancer and has been shown to play a pivotal role in initial transformation, disease progression, and metastatic dissemination of cancer. Additionally, previous studies have demonstrated elevated Rac signaling is capable of conferring resistance to both antiestrogen and HER2 targeted therapies, suggesting a common escape mechanism.
Rac is a member of the Rho GTPase family, which consists of Rho, Rac, and CDC42. As with other family members, Rac alternates between an inactive GDP-bound state and an active GTP-bound form that is capable of binding downstream effectors. Because the affinity for GDP is very strong and the intrinsic rate of GTP hydrolysis is very slow, Rac requires the aid of guanine nucleotide exchange factors (GEFs) that facilitate GDP dissociation allowing GTP replacement and of GTPase activation proteins (GAPs) that stimulate the intrinsic rate of GTP hydrolysis. External stimuli activate transmembrane receptor tyrosine kinases, G-protein coupled receptors, and integrins, activate Rac GEFs initiating Rac signal transduction. Rac activation canonically results in reorganization of the cytoskeleton resulting in increased phagocytosis, mesenchymal-like migration, axonal growth, adhesion and differentiation of various cell types. In addition to cytoskeletal rearrangements, Rac activation also results in enhanced gene expression, translation, cellular proliferation, and cell survival by activating numerous downstream effectors such as the p21-activated kinases (PAKs). The multitude of both upstream activators and downstream effectors highlight that Rac is a key signaling integrator whose activity controls numerous cellular phenotypes. Because Rac is a cytosolic molecular switch that becomes activated when bound to GTP, small molecules that prevent GTP binding to Rac and/or block the binding of Rac to downstream effectors will inhibit downstream signal propagation.
Rac is both overexpressed and hyperactive in a variety of different cancers (including breast cancer) driving malignant transformation by enhancing tumorigenesis, the angiogenic switch, invasion and metastatic dissemination. Under normal physiologic conditions, Rac activity is controlled both temporally and spatially by post-translational modifications. In breast cancer, overexpression/mutation of growth factor receptors such as EGFR and HER2 activate Rac GEFs resulting in Rac activation. Furthermore, numerous Rac GEFs such as Dock4, Tiam1, Trio, Vav3, PREX1 and PREX2 have been shown to be overexpressed in breast cancer. Oncogenic variants of Rac itself have also been identified. The recurring Rac1 P29S/L mutation observed in melanoma and Rac1 A159V mutation in head and neck cancer results in constitutive activation of Rac1. Less frequent mutations such as Rac1 C157Y and N92I have been reported in lung adenocarcinoma and the HT1080 fibrosarcoma cell line.
Therefore, efficacious pan-Rac inhibitors are desired for use as potentially valuable therapeutic agents for the treatment of cancer and other diseases that show a dependence on Rac protein signaling.